Tumor-associated antigens located at the cell surface serve as potential targets for the immune system of the host and may be important in establishing or maintaining malignant phenotype of the tumor cell. The long-term objective of this research is to understand the genetic mechanisms by which the tumor cell regulates expression of its cell-surface antigens. To accomplish this aim, we will study several normal and tumor-associated antigens of murine lymphomas in order to define and understand the mechanism of action of the genes which are critical in the regulation of their expression on the cell surface. The general approach is to isolate somatic cell mutants that show abnormal cell surface expression of particular cell surface molecules and to characterize the defects in molecular terms. The Thy-1 and T200 glycoproteins are being characterized in detail. Eight complementation classes of Thy-1- mutants have been isolated. One mutant class, defining a critical post-translational step in Thy-1 glycoprotein biosynthesis, has been characterized in detail. A second class has been shown to represent mutants in the Thy-1 structural gene and several mutants have been analyzed at the nucleic acid level. Mutants of this class have been shown to express Thy-1 glycoprotein. Some, however, do not, and the reason that they do not is under investigation. A third mutant class has properties expected of a regulatory mutation and is being studied at the nucleic acid level. A series of T200- mutants has also been isolated and preliminary genetic characterization is being carried out. Finally, hybrids between Thy-1+ and Thy-1- cell lines are being studied to identify genes which may regulate antigen expression during differentiation. Several gene dosage-dependent regulatory circuits have been identified. Studies are being carried out to determine whether regulation acts at the level of gene transcription. (AG)